1. Field of the Invention
The present invention is directed to a method for treating tuberculosis in a mammal which comprises administering to the mammal a therapeutically effective amount of an inhibitor compound that inhibits an enzyme in the branched chain amino acid biosynthetic pathway in Mycobacterium tuberculosis.
2. Description of the Background
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are referenced in the following text and respectively grouped in the appended bibliography.
Tuberculosis (TB) kills 2.5 million people annually and the World Health Organization estimated that, at the current rate of increase, there will be 4 million tuberculosis deaths worldwide per year by the year 2005 (Bloom and Murray, 1992). In addition, the percentage of clinical tuberculosis isolates that are resistant to the first-line drugs isoniazid and rifampicin has increased substantially (Collins, 1993; Jacobs, 1994). Outbreaks of drug-resistance tuberculosis have occurred in correctional facilities, hospitals, and urban areas in the United States. Most of the drug-resistant tuberculosis has occurred in patients who are co-infected with HIV and the mortality rate associated with these infections is as high as 90% (Collins, 1993; Dunlap and Kimerling, 1994). The rise in tuberculosis cases in the United States is also attributed to an increase in immigration from areas of the world in which tuberculosis infection rates are high (Dunlap and Kimerling, 1994; Hutchins and Hershfield, 1993). A major part of the strategy to overcome the worldwide tuberculosis problem will be the development of new therapeutic agents to treat this disease (Collins, 1993).
Historically, antimycobacterial drugs were discovered by screening compounds for inhibition of growth of the bacteria. The search for the target site of these compounds occurred after they were shown to be useful antibiotics. For example, isoniazid was introduced as an antimycobacterial drug in 1952 but its target site was not elucidated until 1995 (Dressen et al., 1995). Furthermore, the mechanism of toxicity of isoniazid is still not understood because it is converted by the bacteria to a toxic metabolite that has not been identified (Dressen et al., 1995; Zang and Young, 1993). The target sites of two other first-use drugs, ethambutol (Silve et al., 1993; Takayama and Kilburn, 1989; Wolucka et al., 1994) and pyrazinamide (Heifets et al., 1989) are not yet defined.
Using transposon mutagenesis, McAdam et al. isolated two leucine auxotrophic strains and one methionine auxotrophic strain of M. bovis (BCG) (McAdam et al., 1995). Infection of mice with the auxotrophic strains was compared with the parent strain. On day 30 of infection, there were 100-fold more colony-forming units (cfu) of BCG in the spleens and lungs of mice infected with the parent strain than in mice infected with the leucine auxotrophic strains. Conversely, the numbers of colony forming units measured in mice infected with the methionine auxotrophic strain were comparable to the parent strain. Both of the leucine auxotrophic strains contained transposon insertions in the leuD gene, which encodes a subunit of isopropylmalate isomerase (IPMI) (see FIG. 1).
The discovery that the phytotoxic effect of sulfonyl urea herbicides is due to inhibition of the first step in branched chain amino acid synthesis focused a great deal of research on this pathway for development of new herbicides (Hawkes et al., 1989; Schloss, 1994; Schloss et al., 1988). This effort has led to discovery of a large number of branched chain amino acid pathway inhibitors, some of which are produced in large quantity for commercial use.